Functional recovery is obtained in the injured peripheral nervous system, whereas neural regeneration in an injured central nervous system (CNS) is abortive. Regeneration in an injured CNS can be induced by grafted neural tissues, and it appears to be dependent on the grafts' glial cell composition: Schwann cells and embryonic CNS support whereas adult astrocytes inhibit neural regeneration. The objective of this project is to experimentally assess the working hypothesis that a localized proteolytic activity is an essential process in achieving successful repair in a damaged nervous system. Namely, general proteolytic activity can lead to tissue destruction, whereas localized proteolysis, e.g., plasmin-generating system which is expressed by the cells that support regeneration in a highly controlled manner, will remove only the unwanted tissue in the path of regenerating axons. The plasmin-generating system is a serum and extracellular component; it is composed of plasminogen and the specific protease, plasminogen activator (PA), which activates plasminogen to generate the potent protease plasmin. This hypothesis is based on data found in my laboratory that both the developing CNS, the differentiating but not the mature astrocytes and the proliferating Schwann cell populations express extracellular PA activity. Furthermore, the Schwann cell expresses this activity predominantly at those stages when, as was shown in other studies, it supports neuronal regeneration. Research will focus on attempts to verify the working hypothesis. Two model systems of a regenerating nervous system will be utilized: peripheral--the sciatic nerve, and central--the olfactory bulb with regeneration induced within a T-shaped silicone chamber grafted into it. Assuming that localized proteolysis is essential, any treatment which will inhibit this activity should intervene and prevent the regenerating process. Whereas, any other cell type which produces this specific proteolytic activity, i.e., premature astrocyte or tumor cell lines, should support neural regeneration when implanted in the injured tissue.
The specific aims of the project are to biochemically manipulate regeneration in the model systems by (A) treatment with protease inhibitors, (B) elimination, by X-irradiation, of the cells which produce the PA (Schwann cells), and (C) supplementing the PA deficient system with PA activity, i.e., introducing PA producing cells (e.g., tumor cell lines) or resin-immobilized PA. If the hypothesis is verified, novel avenues will be opened for research into possible therapeutic procedures to induce repair in any injured CNS, by a local application of PA at the site of injury.
| Kalderon, N; Alfieri, A A; Fuks, Z (1990) Beneficial effects of x-irradiation on recovery of lesioned mammalian central nervous tissue. Proc Natl Acad Sci U S A 87:10058-62 |
| Kalderon, N; Ahonen, K; Fedoroff, S (1990) Developmental transition in plasticity properties of differentiating astrocytes: age-related biochemical profile of plasminogen activators in astroglial cultures. Glia 3:413-26 |
| Kalderon, N (1988) Differentiating astroglia in nervous tissue histogenesis/regeneration: studies in a model system of regenerating peripheral nerve. J Neurosci Res 21:501-12 |
